According to the American Cancer Society about 494,000 people died from cancer in the United States in 1988. One of every five deaths from all causes in the United States is from cancer. Although chemotherapy has become one of the principal methods of treating cancer, the rate at which new drugs have become available for use in cancer chemotherapy has declined in recent years as reported by Horowitz et al. "Phase II Testing of Melphalan in Children with Newly Diagnosed Rhabdomyosarcoma: A Model for Anticancer Drug Development", Journal of Clinical Oncology, Vol. 6, No. 2, pp. 308-314 (1988). Accordingly, there is a substantial need for new drugs which are effective in inhibiting the growth of tumors.
To be particularly useful, a new chemotherapeutic agent should have a wide spectrum of activity, a large therapeutic index, and be chemically stable and compatible with other agents. Additionally, it would be beneficial for the new agent to have oral activity so that initial treatment and subsequent maintenance therapy is more convenient and less traumatic to the patient.
It has now been found that certain N-phenyl-N'-alkylsulfonylureas are particularly useful in the treatment of solid tumors. These compounds are relatively nontoxic and provide an excellent therapeutic index.
Some N,N'-diarylsulfonylureas have been reported as being active antitumor agents e.g., U.S. Pat. No. 4,845,128 of Harper et al. (1989) and Grindey et al. American Association of Cancer Research, Vol. 27, pp. 277 (1986). There is no suggestion in these references of the N-phenyl-N'-sulfonylureas of the instant application or that these compounds would be useful as antitumor agents.
Certain arylalkylsulfonylureas have been reported in the literature. U.S. Pat. No. 2,979,437 of McLamore et al. (1961) discloses compounds of the general formula RCH.dbd.CHSO.sub.2 NHCONHR' in which R can be a phenyl or substituted phenyl and R' can be p-chloro- or p-bromophenyl as having hypoglycemic activity. Chemical Abstracts, Vo. 54, 5532d (1960) cites an article by Palazzo et al. (Farmaco. Ed. Sci., 14, 358-62 (1959)) which discloses N-(p-chlorophenyl)-N'-butylsulfonylurea. The compound is disclosed as producing hypoglycemia in rabbits after oral administration.
Giorgetti in Bulletin De La Societe Chimique. De France, 1971, No. 10, pp. 3600 discloses the preparation of a sulfonylurea with formula CH.sub.2 .dbd.CHSO.sub.2 NHCONHR where R is 3,4-dichlorophenyl.
Holland in U.S. Pat. No. 3,983,107 (1976) also discloses certain 2-phenylethenesulfonamide derivatives of the general formula RCH.dbd.CHSO.sub.2 NHCONR.sup.1 R.sup.2 where R is a phenyl and R.sup.1 and R.sup.2 can be hydrogen or a substituted phenyl. These compounds are disclosed as being useful for reducing elevated serum lipid levels in mammals.
Hainaut et al. in U.S. Pat. No. 4,045,209 (1977) disclose compounds of the formula XSO.sub.2 (CH.sub.2).sub.n NCH.sub.3 --CONYR where n is 0 or 1, X can be a C.sub.1 -C.sub.6 alkyl, Y can be hydrogen and R is a phenyl group which can be substituted with hydrogen, chlorine or bromine. These compounds having a methyl substituent on the nitrogen adjacent to the sulfonyl group are disclosed as being useful as herbicides.
None of these references suggest or disclose the antitumor activity of the sulfonylurea compounds of the instant invention. Additionally, there is no suggestion or disclosure of the claimed compounds of the instant invention.